The proposed research will examine the role of Sonic hedgehog (Shh) in penile development and the dysregulation of this pathway in diabetes induced erectile dysfunction. Shh is a secreted glycopeptide that is critically relevant in mesenchymal-epithelial interaction in developing tissues. We will show preliminary evidence that Shh signaling in the corpora is neurally regulated during penile development and in the adult, and propose to determine the impact of diabetic neuropathy on the expression and activity of Shh in corporal bodies. Diabetes mellitus is a common risk factor for erectile dysfunction, which is a devastating pathologic development that effects 10-30 million American men and costs in excess of $150 million for inpatient urologic care alone (1985 dollars). Although angiopathy and neuropathy are frequent complications in the natural history of DM, the precise cause of diabetic impotence remains unknown. We will examine the hypothesis that neural Shh signaling is elemental in establishing and maintaining normal penile morphology and that erectile dysfunction associated with diabetic neuropathy results from disruption of the homeostatic functions of the Shh pathway. The power of this proposal is its potential to provide novel and critically important insight into the mechanism of diabetes induced erectile function. This may provide the basis for new treatments to prevent or treat this complication and may provide collateral insights into other neurovascular complications of diabetes. The proposed experiments are ideally suited to satisfy the goals of this RFA since novel and innovative technology is utilized to advance our current understanding of one aspect of urogenital development, specifically how neural Shh signaling during postnatal morphogenesis of the penis establishes corporal cavernosal integrity required for erection. Re-establishment of this signaling pathway offers great promise for erectile dysfirnction treatment. Knowledge gained in these studies may be applied to investigate the role of neural input in establishing tissue identity and examining the function of neuropathy in disease.